Oral epithelial cells orchestrate innate type 17 responses to <i>Candida albicans</i> through the virulence factor candidalysin

Abstract

<i>Candida albicans</i> is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of <i>C. albicans</i> hyphae into oral epithelium is an essential virulence trait. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to <i>C. albicans</i> During the innate response, IL-17 is produced by γδ T cells and a poorly understood population of innate-acting CD4⁺ αβ T cell receptor (TCRαβ)⁺ cells, but only the TCRαβ⁺ cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, as evidenced by <i>Nur77</i>^<i>eGFP</i> mice that report antigen-specific signaling through the TCR. Rather, the expansion of innate TCRαβ⁺ cells was driven by both intrinsic and extrinsic IL-1R signaling. Unexpectedly, there was no requirement for CCR6/CCL20-dependent recruitment or prototypical fungal pattern recognition receptors. However, <i>C. albicans</i> mutants that cannot switch from yeast to hyphae showed impaired TCRαβ⁺ cell proliferation and <i>Il17a</i> expression. This prompted us to assess the role of candidalysin, a hyphal-associated peptide that damages oral epithelial cells and triggers production of inflammatory cytokines including IL-1. Candidalysin-deficient strains failed to up-regulate <i>Il17a</i> or drive the proliferation of innate TCRαβ⁺ cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1α/β and other cytokines. Thus, IL-17 and <i>C. albicans</i>, via secreted candidalysin, amplify inflammation in a self-reinforcing feed-forward loop. These findings challenge the paradigm that hyphal formation per se is required for the oral innate response and demonstrate that establishment of IL-1- and IL-17-dependent innate immunity is induced by tissue-damaging hyphae.